7d4p
From Proteopedia
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==Structure of human TRPC5 in complex with clemizole== | ==Structure of human TRPC5 in complex with clemizole== | ||
| - | <StructureSection load='7d4p' size='340' side='right'caption='[[7d4p]]' scene=''> | + | <StructureSection load='7d4p' size='340' side='right'caption='[[7d4p]], [[Resolution|resolution]] 2.70Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7D4P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7D4P FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7d4p]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7D4P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7D4P FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7d4p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d4p OCA], [https://pdbe.org/7d4p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7d4p RCSB], [https://www.ebi.ac.uk/pdbsum/7d4p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7d4p ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GX0:1-[(4-chlorophenyl)methyl]-2-(pyrrolidin-1-ylmethyl)benzimidazole'>GX0</scene>, <scene name='pdbligand=POV:(2S)-3-(HEXADECANOYLOXY)-2-[(9Z)-OCTADEC-9-ENOYLOXY]PROPYL+2-(TRIMETHYLAMMONIO)ETHYL+PHOSPHATE'>POV</scene>, <scene name='pdbligand=PTY:PHOSPHATIDYLETHANOLAMINE'>PTY</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</scene>, <scene name='pdbligand=YZY:(2S)-2-(HEXADECANOYLOXY)-3-HYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>YZY</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TRPC5, TRP5 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7d4p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d4p OCA], [https://pdbe.org/7d4p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7d4p RCSB], [https://www.ebi.ac.uk/pdbsum/7d4p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7d4p ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [[https://www.uniprot.org/uniprot/TRPC5_HUMAN TRPC5_HUMAN]] Thought to form a receptor-activated non-selective calcium permeant cation channel. Probably is operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Has also been shown to be calcium-selective (By similarity). May also be activated by intracellular calcium store depletion. Mediates calcium-dependent phosphatidylserine externalization and apoptosis in neurons via its association with PLSCR1 (By similarity).[UniProtKB:Q9QX29]<ref>PMID:16284075</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | TRPC5 channel is a nonselective cation channel that participates in diverse physiological processes. TRPC5 inhibitors show promise in the treatment of anxiety disorder, depression, and kidney disease. However, the binding sites and inhibitory mechanism of TRPC5 inhibitors remain elusive. Here, we present the cryo-EM structures of human TRPC5 in complex with two distinct inhibitors, namely clemizole and HC-070, to the resolution of 2.7 A. The structures reveal that clemizole binds inside the voltage sensor-like domain of each subunit. In contrast, HC-070 is wedged between adjacent subunits and replaces the glycerol group of a putative diacylglycerol molecule near the extracellular side. Moreover, we found mutations in the inhibitor binding pockets altered the potency of inhibitors. These structures suggest that both clemizole and HC-070 exert the inhibitory functions by stabilizing the ion channel in a nonconductive closed state. These results pave the way for further design and optimization of inhibitors targeting human TRPC5. | ||
| + | |||
| + | Structural basis for human TRPC5 channel inhibition by two distinct inhibitors.,Song K, Wei M, Guo W, Quan L, Kang Y, Wu JX, Chen L Elife. 2021 Mar 8;10. pii: 63429. doi: 10.7554/eLife.63429. PMID:33683200<ref>PMID:33683200</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7d4p" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Chen L]] | + | [[Category: Chen, L]] |
| - | [[Category: Guo W]] | + | [[Category: Guo, W]] |
| - | [[Category: Song K]] | + | [[Category: Song, K]] |
| - | [[Category: Wei M]] | + | [[Category: Wei, M]] |
| + | [[Category: Clemizole]] | ||
| + | [[Category: Metal transport]] | ||
| + | [[Category: Trpc]] | ||
| + | [[Category: Trpc5]] | ||
Revision as of 12:50, 13 October 2021
Structure of human TRPC5 in complex with clemizole
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Categories: Human | Large Structures | Chen, L | Guo, W | Song, K | Wei, M | Clemizole | Metal transport | Trpc | Trpc5
